EP1991228A1 - Treatment of prevention of valvular heart disease with flibanserin - Google Patents

Treatment of prevention of valvular heart disease with flibanserin

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Publication number
EP1991228A1
EP1991228A1 EP07726495A EP07726495A EP1991228A1 EP 1991228 A1 EP1991228 A1 EP 1991228A1 EP 07726495 A EP07726495 A EP 07726495A EP 07726495 A EP07726495 A EP 07726495A EP 1991228 A1 EP1991228 A1 EP 1991228A1
Authority
EP
European Patent Office
Prior art keywords
acid
flibanserin
heart disease
valvular heart
valvular
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07726495A
Other languages
German (de)
French (fr)
Inventor
Angelo Ceci
Peter Bette
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Priority to EP07726495A priority Critical patent/EP1991228A1/en
Publication of EP1991228A1 publication Critical patent/EP1991228A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin.
  • Flibanserin shows affinity for the 5-HT1 A and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment or prevention of a variety of diseases, for instance depression, schizophrenia, and anxiety.
  • the term ..Valvular heart disease relates to any dysfunction or abnormality of one or more of the heart's four valves, including the mitral valve and aortic valve of the left heart, and the tricuspid valve and pulmonic valve of the right heart.
  • the four valves overlaps made of tissue
  • the four valves prevent blood from flowing backwards into the ventricles and while allowing the forward flow of blood into the lung and peripheral circulation in the course of the cardiac action.
  • valvular heart disease is responsible for nearly 20,000 deaths each year in the United States and is a contributing factor in about 42,000 deaths. The majority of these cases involve disorders of the aortic valve (63 percent) and the mitral valve (14 percent). Deaths due to pulmonic and tricuspid valve disorders are more rare (0.06 percent and 0.01 percent, respectively).
  • Valvular Stenosis There are a number of types of valvular heart disease, including: a) Valvular Stenosis:
  • the defective valve can interfere with the smooth passage of blood through it leading to increased resistance.
  • the diagnosis may be aortic stenosis, mitral stenosis, pulmonic stenosis or tricuspid stenosis.
  • the nature and severity of the leakage may increase the blood volume that is moved during each cardiac cycle or even keep the heart from circulating an adequate amount of blood.
  • the diagnosis may be aortic regurgitation, mitral regurgitation, pulmonary regurgitation or tricuspid regurgitation.
  • the diagnosis may be aortic atresia, mitral atresia, pulmonary atresia or tricuspid atresia.
  • the instant invention relates to a method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • the instant invention relates to a method for the treatment or prevention of Valvular stenosis comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • the instant invention relates to a method for the treatment or prevention of Valvular Regurgitation comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • the instant invention relates to a method for the treatment or prevention of Atresia of one of the Valves comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • the instant invention relates to a method for the treatment or prevention of Mitral Valve Prolapse comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • Another embodiment of the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, for the preparation of a medicament for the treatment or prevention of any of the aforementioned conditions.
  • Flibanserin can optionally be used in form of its pharmaceutically acceptable acid addition salts.
  • Suitable acid addition salts include for example those of the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularity the hydrochloride, are preferred. If flibanserin is used in form of the free base, it is preferably used in form of flibanserin polymorph A as disclosed in WO 03/014079.
  • Flibanserin optionally used in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form.
  • the composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
  • the active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80.
  • the compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
  • the dosis range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg Flibanserin.
  • Each dosage unit may conveniently contain from 0,01 mg to 100 mg Flibanserin, preferably from 0,1 to 50 mg.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets may also comprise several layers.
  • Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core may also consist of a number of layers.
  • the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • a sweetener such as saccharine, cyclamate, glycerol or sugar
  • a flavour enhancer e.g of. a flavouring such as vanilline or orange extract.
  • suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • the finely ground active substance, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of Polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starchand the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • flibanserin hydrochloride 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg
  • the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
  • the sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
  • the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
  • the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen.
  • convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine .
  • the tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is screened and dried.
  • the dry granules are screened and mixed with magnesium stearate.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
  • the hard fat is melted.
  • the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.
  • flibanserin is administered in form of specific film coated tablets.
  • examples of these preferred formulations are listed below.
  • the film coated tablets listed below can be manufactured according to procedures known in the art (see hereto WO 03/097058).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
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Abstract

The invention relates to a method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin.

Description

TREATMENT OF PREVENTION OF VALVULAR HEART DISEASE WITH FLIBANSERIN
The invention relates to a method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin.
Description of the invention
The compound 1 -[2-(4-(3-trifluoromethyl-phenyl)piperazin-1 -yl)ethyl]-2,3-dihydro-1 H- benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochloride in European Patent Application EP-A-526434 and has the following chemical structure:
Flibanserin shows affinity for the 5-HT1 A and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment or prevention of a variety of diseases, for instance depression, schizophrenia, and anxiety.
Now, experiments provided evidence, that flibanserin can not only be used for the aforementioned diseases but also for the treatment or prevention of Valvular Heart Disease.
Within the present invention, the term ..Valvular heart disease" relates to any dysfunction or abnormality of one or more of the heart's four valves, including the mitral valve and aortic valve of the left heart, and the tricuspid valve and pulmonic valve of the right heart. In a normally functioning heart, the four valves (flaps made of tissue) prevent blood from flowing backwards into the ventricles and while allowing the forward flow of blood into the lung and peripheral circulation in the course of the cardiac action.
According to the American Heart Association's 2004 Heart and Stroke Statistical Update, valvular heart disease is responsible for nearly 20,000 deaths each year in the United States and is a contributing factor in about 42,000 deaths. The majority of these cases involve disorders of the aortic valve (63 percent) and the mitral valve (14 percent). Deaths due to pulmonic and tricuspid valve disorders are more rare (0.06 percent and 0.01 percent, respectively).
There are a number of types of valvular heart disease, including: a) Valvular Stenosis:
A condition in which there is a narrowing, stiffening, thickening, fusion or blockage of one or more valves of the heart. As a result, the defective valve can interfere with the smooth passage of blood through it leading to increased resistance. Depending on which valve is affected, the diagnosis may be aortic stenosis, mitral stenosis, pulmonic stenosis or tricuspid stenosis.
b) Valvular Regurgitation:
A condition in which blood leaks backwards because one or more of the heart's valves is closing improperly. The nature and severity of the leakage, in turn, may increase the blood volume that is moved during each cardiac cycle or even keep the heart from circulating an adequate amount of blood. Depending on which valve is affected, the diagnosis may be aortic regurgitation, mitral regurgitation, pulmonary regurgitation or tricuspid regurgitation.
c) Atresia of one of the valves:
A serious condition in which one of the valves have failed to develop properly and is completely closed at birth. Depending on which valve is affected, the diagnosis may be aortic atresia, mitral atresia, pulmonary atresia or tricuspid atresia.
d) Mitral Valve Prolapse:
A common and rarely serious condition in which the two flaps of the mitral valve (located between the left atrium and the left ventricle) can not close properly, and may result in blood leaking back into the left atrium (mitral valve regurgitation). It is due to either one (or both) of the flaps being too large, or because the muscle "hinges" of the flaps are too long Accordingly, the instant invention relates to a method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
In another embodiment, the instant invention relates to a method for the treatment or prevention of Valvular stenosis comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
In another embodiment, the instant invention relates to a method for the treatment or prevention of Valvular Regurgitation comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
In another embodiment, the instant invention relates to a method for the treatment or prevention of Atresia of one of the Valves comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
In another embodiment, the instant invention relates to a method for the treatment or prevention of Mitral Valve Prolapse comprising the administration of a therapeutically effective amount of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
Another embodiment of the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, for the preparation of a medicament for the treatment or prevention of any of the aforementioned conditions.
Flibanserin can optionally be used in form of its pharmaceutically acceptable acid addition salts. Suitable acid addition salts include for example those of the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularity the hydrochloride, are preferred. If flibanserin is used in form of the free base, it is preferably used in form of flibanserin polymorph A as disclosed in WO 03/014079.
Flibanserin, optionally used in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80. The compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient. The dosis range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg Flibanserin. Each dosage unit may conveniently contain from 0,01 mg to 100 mg Flibanserin, preferably from 0,1 to 50 mg. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. The Examples which follow illustrate the present invention without restricting its scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
flibanserin hydrochloride 100 mg lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg
740 mg
The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of Polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starchand the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
B) Tablets per tablet
flibanserin hydrochloride 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg
400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
C) Coated tablets per coated tablet
flibanserin hydrochloride 5 mg corn starch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 mg
80 mg
The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine . The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
D) Capsules per capsule
Flibanserin hydrochloride 150 mg
Corn starch 268 ■5 mg
Magnesium stearate 1 ■5 mg
420 mg The substance and corn starch are mixed and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.
E) Ampoule solution
flibanserin hydrochloride 50 mg sodium chloride 50 mg water for inj. 5 ml
The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
F) Suppositories
flibanserin hydrochloride 50 mg solid fat 1650 mg
1700 mg
The hard fat is melted. At 400C the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.
In a particular preferred embodiment of the instant invention, flibanserin is administered in form of specific film coated tablets. Examples of these preferred formulations are listed below. The film coated tablets listed below can be manufactured according to procedures known in the art (see hereto WO 03/097058). G) Film coated tablet Core
Coating
H) Film coated tablet Core
Coating
Total Film coated tablet 255.000
I) Film coated tablet Core
Coating
J) Film coated tablet Core Coating
K) Film coated tablet
Core
Coating
L) Film coated tablet
Core
Coating

Claims

Patent Claims
1 ) A method for the treatment or prevention of Valvular Heart Disease comprising the administration of a therapeutically effective amount of flibanserin optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
2) A method according to claim 1 wherein the Valvular Heart Disease is a Valvular Stenosis.
3) A method according to claim 1 wherein the Valvular Heart Disease is a Valvular Regurgitation.
4) A method according to claim 1 wherein the Valvular Heart Disease is a Atresia of one of the Valves.
5) A method according to claim 1 wherein the Valvular Heart Disease is a Mitral Valve Prolapse.
6) A method according to one or more of the claims 1 to 5, characterized in that flibanserin is applied in form of a pharmaceutically acceptable acid addition salt selected from the salts formed by the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid, citric acid, and mixtures thereof.
7) A method according to one or more of the claims 1 to 5, characterized in that flibanserin is applied in form of its polymorph A.
8) A method according to one or more of the claims 1 to 7, characterized in that flibanserin is applied in a dosis range between 0.1 to 400 mg per day.
EP07726495A 2006-02-28 2007-02-26 Treatment of prevention of valvular heart disease with flibanserin Withdrawn EP1991228A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07726495A EP1991228A1 (en) 2006-02-28 2007-02-26 Treatment of prevention of valvular heart disease with flibanserin

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06004065 2006-02-28
EP07726495A EP1991228A1 (en) 2006-02-28 2007-02-26 Treatment of prevention of valvular heart disease with flibanserin
PCT/EP2007/051780 WO2007099070A1 (en) 2006-02-28 2007-02-26 Treatment of prevention of valvular heart disease with flibanserin

Publications (1)

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EP1991228A1 true EP1991228A1 (en) 2008-11-19

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EP (1) EP1991228A1 (en)
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CA (1) CA2642368A1 (en)
WO (1) WO2007099070A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7183410B2 (en) * 2001-08-02 2007-02-27 Bidachem S.P.A. Stable polymorph of flibanserin
US20030060475A1 (en) * 2001-08-10 2003-03-27 Boehringer Ingelheim Pharma Kg Method of using flibanserin for neuroprotection
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
UA78974C2 (en) 2001-10-20 2007-05-10 Boehringer Ingelheim Pharma Use of flibanserin for treating disorders of sexual desire
US20040048877A1 (en) * 2002-05-22 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions containing flibanserin
US20050239798A1 (en) * 2004-04-22 2005-10-27 Boehringer Ingelheim Pharmaceuticals, Inc. Method for the treatment of premenstrual and other female sexual disorders
JP2009503020A (en) * 2005-08-03 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Use of flibanserin in the treatment of obesity
CA2626134C (en) 2005-10-29 2013-12-24 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
US20070105869A1 (en) * 2005-11-08 2007-05-10 Stephane Pollentier Use of flibanserin for the treatment of pre-menopausal sexual desire disorders
MX2008013827A (en) * 2006-05-09 2008-11-10 Boehringer Ingelheim Int Use of flibanserin for the treatment of post-menopausal sexual desire disorders.
EP2037927B1 (en) * 2006-06-30 2010-01-27 Boehringer Ingelheim International GmbH Flibanserin for the treatment of urinary incontinence and related diseases
WO2008006838A1 (en) * 2006-07-14 2008-01-17 Boehringer Ingelheim International Gmbh Use of flibanserin for the treatment of sexual disorders in females
JP5793828B2 (en) 2006-08-14 2015-10-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Formulation of flibanserin and method for producing the same
CL2007002214A1 (en) 2006-08-14 2008-03-07 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION IN THE FORM OF COMPRESSED, WHERE AT LEAST THE LENGTH OF THE COMPRESSED IN THE PREVIOUS STATE OF THE APPLICATION IS AT LEAST 7/12 OF THE PILOR DIAMETER OF THE PATIENT AND AFTER INGERING IT IN THE FOOD STATE, THE LENGTH OF THE COMP
KR20090045945A (en) * 2006-08-25 2009-05-08 베링거 인겔하임 인터내셔날 게엠베하 Controlled Release System and Manufacturing Method Thereof
WO2008090742A1 (en) * 2007-01-23 2008-07-31 National University Corporation Hokkaido University Non-human animal for eye disease model
CL2008002693A1 (en) * 2007-09-12 2009-10-16 Boehringer Ingelheim Int Use of flibanserin for the treatment of selected vasomotor symptoms of hot flashes, night sweats, mood swings, and irritability
WO2009120717A2 (en) * 2008-03-24 2009-10-01 Medivation Technologies, Inc. Pyrido [3, 4-b] indoles and methods of use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1251144B (en) * 1991-07-30 1995-05-04 Boehringer Ingelheim Italia BENZIMIDAZOLONE DERIVATIVES
CH692199A8 (en) * 1997-10-09 2002-06-14 Cermol S.A. PYRIDIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS
UA76767C2 (en) * 2001-08-02 2006-09-15 Бідакем С.П.А. Stable polymorph modification of flibanserin, method for industrial production thereof and use thereof for preparing medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007099070A1 *

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